Patent GB-797258-A (GB)
Title: 3-substituted indoles
IPC: C07D209/24
Filed: 1956-03-21
Abstract: The invention comprises 3-(2-amino-1-hydroxy-ethyl)-indoles which are 1-"dehydro" compounds, i.e. have no hydrogen atom attached to the nitrogen atom of the indole ring, and which have the formula <FORM:0797258/IV (b)/1> wherein R4 is an alkyl, aryl or aralkyl radical containing not more than 20 carbon atoms, R2 is hydrogen or an alkyl, aryl or aralkyl radical containing not more than 15 carbon atoms, R4 is a radical containing not more than 15 carbon atoms and is hydroxy, dialkylamino, methylol, aminomethyl, halogen, alkyl, aryl, aralkyl, aryloxy, a fused arylene radical, a benzyloxy radical or an alkoxy radical, n is zero or an integer from 1 to 4 and Z is a primary, secondary or tertiary amino radical, and acid addition and quaternary salts of these compounds.  The invention also comprises a process for the preparation of 1-dehydro-3-(2-amino-1-hydroxy-ethyl)-indoles by reducing with lithium aluminium hydride a 1-dehydro-3-indoleglycolamide or a 1-dehydro-3-glyoxylamide for example a compound of the formula <FORM:0797258/IV (b)/2> wherein R2 is hydrogen, aryl, aralkyl or a lower-alkyl radical of 1-8 carbon atoms, n is zero or an integer from 1 to 4, R3 is a carboxy, cyano, dialkylamino, lower carbalkoxy of 1-8 carbon atoms, halogen, lower alkyl, aryl, aralkyl, aryloxy, lower-alkoxy containing 1-8 carbon atoms, benzyloxy, an acyloxy radical wherein the acyl substituent is from an organic carboxylic acid, or a fused arylene radical, R5 is an alkyl, aryl or aralkyl group, <FORM:0797258/IV (b)/3> is a primary, secondary or tertiary amide radical and Y is a <FORM:0797258/IV (b)/4> group.  The reduction is suitably carried out in an inert solvent suitably by heating to the boiling point of the solvent used.  The product may be isolated by hydrolysing the reaction mixture with aqueous ether followed by dilute alkali, decanting the solvent layer and evaporating the solvent.  Reduction of 1-dehydro-3-indoleglyoxylamides wherein R3 is an acyloxy, cyano, carboxy, or lower carbalkoxy radical results in the conversion of these substituents to a hydroxy, aminomethyl, methylol and methylol radical respectively.  The reduction may also be effected in a stepwise manner whereby a 1-dehydro-3-indoleglyoxylamide is partially reduced to a carbinol group by means of reducing agents other than lithium aluminium hydride, e.g. sodium borohydride, lithium borohydride, aluminium amalgam or catalytic hydrogenation with a platinum oxide catalyst, and the resulting 1-dehydro-3-indoleglycolamide is then reduced with lithium aluminium hydride to give the desired 1-dehydro-3-(2-amino-1-hydroxyethyl)-indole.  Preferred products include the 1 - alkyl - 3 - (2 - dialkylamino - 1 - hydroxyethyl) - indoles such as 1 - ethyl - 3 - (2 - dimethylamino - 1 - hydroxyethyl) - indole and 1 - methyl - 3 - (2 - dimethylamino - 1 - hydroxyethyl) - indole, 1 - alkyl - 3 - (2 - alkylamino - 1 - hydroxyethyl) - indoles such as 1-methyl - 3 - (2 - methylamino - 1 - hydroxy - ethyl)-indole and 1 - ethyl - 3 - (2 - methyl - amino - 1 - hydroxyethyl) - indole, 1 - methyl-3-(2 - morpholino - 1 - hydroxyethyl) - indole and salts of these compounds.  The salts, which may be prepared from the free bases by conventional methods may suitably be, for example, hydrochlorides, hydrobromides, sulphates, phosphates, pyruvates, acetates, tartrates, citrates, benzoates, trichloroacetates or quaternary salts such as methiodides, ethiodides and benzyl chlorides.  The products are used as hypotensive and diuretic agents.  The fluosilicic acid salts are used as mothproofing agents.  Examples describe the preparation by reduction of the corresponding glyoxylamides or glycolamides of 1 - substituted - 3 - (b  - substituted - a  - hydroxyethyl)-indoles in which the nuclear substituents and the b -substituent on the 3-ethyl group are (1) 1 - methyl, b  - methylamino; (2) 1 - methyl, b  - benzylmethylamino; (3) 1 - methyl, b -morpholino; (4) 1 - methyl, b  - benzylamino; (5) and (40) 1 - ethyl, b  - dimethylamino; (6) and (17) 1 - methyl, b  - amino; (7) 1 - methyl, b  - dibenzylamino; (8) 1 - methyl, b  - anilino; (9) 1-methyl, b -dimethylamino; (10) 1-ethyl, b -methylamino; (11) 1-isopropyl, b -dimethylamino; (12) 1-butyl, b -dimethylamino; (13) 1 - hexyl, b  - dimethylamino; (14) 1 - hexadecyl, b -dimethylamino; (15) 1-methyl, b -isopropylamino; (16) 1-methyl, 2-phenyl, b -piperidino; (18) 1-benzyl, b -ethyl; (19) 1-ethyl, 2-ethyl, b -dibutylamino; (20) 1-hexyl, 6-benzyloxy, b -benzylamino; (21) 1-propyl, 2-propyl, 6 - p : p1 - dimethylbenzhydryloxy, b -butylamino; (22) 1 - p - methoxybenzyl, 5-p-methoxybenzyloxy, b  - dimethylamino; (23) 1-octyl, 2-octyl, 6-p-methylbenzyloxy, b -anilino; (24) 1 - p - chlorobenzyl, 6 - p - chlorobenzyl - oxy, b  - propylamino; (25) 1-ethyl, 2-phenyl, 5 - ethoxy, b  - hexamethyleneimino; (26) 1-p-methylbenzyl, 5-hydroxy, 6-hydroxy, b -benzylmethylamino; (27) 1 - phenylethyl, 2 - phenyl, 5-chloro, b -methylamino; (28) 1-p-methylbenzyl, 2-propyl, 6-aminomethylb -benzylamino; (29) 1-decyl, 4-methylol, b -piperidino; (30 1-phenethyl, 2-ethyl, 6-methylol, b -propylamino; (31) 1-octyl, 6-dimethylamino, b -diethylamino; (32) 1-ethyl, 2-phenyl, 5-methyl, b -anilino; (33) 1-benzyl, 2-phenyl, 5-phenyl, b -benzylamino; (34) 1-ethyl, benz-(g), b -dimethylamino; (35) 1-decyl, 5-phenoxy, b -cyclohexylamino; (36) 1-ethyl, 2-p-biphenylyl, b -benzyl-2-ethylhexyl-amino; (37) 1-benzyl, 2-phenyl, 5-chloro, 7-chloro, b -anilino; (38) 1-benzyl, 7-benzyl, b -methylamino and (39) 1-phenyl, b -2 : 2-dimethylpyrrolidino.  The preparation of quaternary salts such as the methobromide of the product of (5) is described.  Starting materials.  1-Dehydro - 3 - indoleglycolamides such as 1-ethyl-n : n-dimethyl-3-indoleglycolamide are made by the reduction of the corresponding glyoxylamide by reducing agents other than lithium aluminium hydride.  1 - Dehydro - 3 - indoleglyoxylamides such as those corresponding to the 3-(2-amino-1-hydroxy-ethyl)-compounds of the examples are made by treating a 1-hydro-3-indolegloxylyl halide with ammonia or a primary or secondary amine to give a 1-hydro-3-indoleglyoxylamide, and introducing a substituent into the 1-position, for example, by reaction with an alkyl or aralkyl halide in the presence of an alkalimetal alkoxide; alternatively a 1-alkyl-, aryl-or aralkylsubstituted indole glyoxylyl halide is aminated to form the desired 1-substituted 3-indoleglyoxylamide.  3-Indoleglyoxylyl halides such as 3-indoleglyoxylyl chloride and the 1-methyl-, 1 - methyl - 2 - phenyl-, 1 - benzyl-, 1 : 2 - diethyl-, 1 - hexyl - 6 - benzyloxy-, 1 : 2-dipropyl - 6 - p : p1 - dimethylbenzhydryloxy-, 1 - p - methoxybenzyl - 5 - p - methoxybenzyloxy-, 1 : 2 - dioctyl - 6 - p - methylbenzyloxy-, 1 - p - chlorobenzyl - 6 - p - chlorobenzyloxy-, 1 - ethyl-2-phenyl - 5 - ethoxy-, 1 - p - methylbenzyl - 5 : 6-diacetoxy-, 1 - phenethyl - 2 - phenyl - 5 - chloro-, 1 - p - methylbenzyl - 2 - propyl - 6 - cyano-, 1-decyl - 4 - carbomethoxy-, 1 - phenethyl - 2 - ethyl-6 - carboxy-, 1 - octyl - 6 - dimethylamino-, 1-ethyl - 2 - phenyl - 5 - methyl-, 1 - benzyl - 2 : 5 - diphenyl-1 - ethyl - 1 - benz - (g)-, 1 - decyl-5-phenoxy-, 1 - ethyl - 2 - biphenylyl-, 1 - benzyl-2-phenyl - 5 : 7 - dichloro - 1 : 7 - dibenzyl-, and 1-phenyl-, derivatives of 3-indoleglyoxylyl chloride are made by the action of an oxalyl halide on the corresponding indole derivatives unsubstituted in the 3-position, and may then be connected into the amides used as starting materials in the examples by the action of the appropriate amine. 1-Alkyl or aralkyl-indoles such as 1 : 2-diethylindole, 1-hexyl-6-benzoyloxyindole, and others corresponding to the 3-indoleglyoxylyl chlorides listed above are made by alkylating or aralkylating the 1-unsubstituted compounds.  The 1 : 3-unsubstituted indoles used as starting materials are made by standard methods, for example 2-propyl-6-p : p1-dimethylbenzhydrylox - indole, 5 - p - methoxybenzyloxyindole, 2 - octyl - 6 - p - methylbenzyloxy - indole, 6 - p - chlorobenzyloxyindole, 2-propyl-6-cyanoindole, 6 - carbomethoxy - indole and 2 - ethyl-6-carboxy-indole, are made by first forming a p : p1 - dimethylbenzhydryloxy-, p - methoxybenzyloxy-, p - methylbenzyloxy-, p - chlorobenzyloxy-, cyano-, carbomethoxy- or carboxy-substituted, 2-nitrobenzaldehyde, condensing this with a 1-nitroalkane to form a 2-nitro-a -alkyl - a - (1 - nitroalkyl) - benzyl alcohol and dehydrating this to form a corresponding 2-nitro - b  - nitro - styrene derivative which is reductively cyclised, for example by means of powdered iron in acetic acid, to form the desired indole. 6-Dimethylamino-indole is made by reacting 6-amino-indole with dimethyl sulphate.  5-Phenoxyindole is made by forming the p-phenoxyphenylhydrazone of pyruvic acid and heating this with zinc chloride to cause decarboxylation ring closure. 7-Benzylindole is made by forming the ortho-benzylphenylhydrazone of ethyl pyruvate which is then cyclized, saponified and decarboxylated.  2-Phenyl-5:7-dichloroindole is made by heating the 2:6-dichlorophenylhydrazone of acetophenone with zinc chloride in nitrobenzene.